Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, anxiety, depression, hypertension, inflammation, cancer and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness. It can contribute to elevated levels of cholesterol in the blood. Because overeating and obesity have become such a problem in the general population, many individuals are now interested in losing weight, reducing weight, and/or maintaining a healthy body weight and lifestyle.
Pro-opiornelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism.
A specific single MC-R that may be targeted for the control of obesity has not yet been identified. To date five distinct MC-R's have been identified, and these are expressed in different tissues. MC-1R is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain, and its inactivation was shown to cause obesity. Evidence has been presented that MC-4R signaling is important in mediating feed behavior. MC-5R is expressed in many tissues, including white fat, placenta, and exocrine glands. A low level of expression of MC-5R is also observed in the brain.
WO 95/28391 discloses CCK or gastrin modulating 1,5 benzodiazepine derivatives, intermediates, pharmaceutical compositions for treating obesity, gall bladder stasis, disorders of pancreatic secretion, methods for treatment and processes for preparing 1,5 benzodiazepine compounds. This reference discloses 1,5-benzodiazepine compounds as CCK-A agonist activity associated with obesity and/or weight loss. This reference does not appreciate that specific benzodiazepines may provide melanocortin-4 agonist activity.
WO 00/33658 discloses methods and compositions for treating a variety of disorders associated with or caused by undesirable body weight, including obesity as well as “wasting disorders.” This reference discloses methods for identification of compounds that preferentially bind to and/or activate peripheral melanocortin receptors and which minimize binding and/or activation of central melanocortin receptors.
There is an on-going need for the development of a melanocortin 4 receptor agonist useful in the treatment of obesity and other associated or related diseases and conditions.
Accordingly, there is provided a novel group of benzodiazepines that exhibit a useful profile of activity as agonists of the MC4 receptor (i.e., MC4R agonist activity). Novel compounds of the invention are useful in the treatment of obesity and other associated diseases and conditions associated with obesity and other diseases/conditions mediated by the MC4 receptor.